JPS58131968A - Thiol ester compound - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI[R<1> is saturated aliphatic or saturated cycloaliphatic acyl wherein the alpha-carbon atom is tertiary or quaternary carbon; A is glycine residue, sarcosine residue, etc.; R<2> is group of formula II (X is -CO, -CS, -CH2, etc.; Y is -CH2-, -S-, -O-, etc.; R4 is OH or alpha-amino acid residue (bonded at the alpha-amino group)]or its pharmacologically permissible salt. EXAMPLE:N-[3-(N-Cyclohexanecarbonyl-D-alanylthio-2-D-methylpropanoyl]- L-prolyl-L-phenylalanire. USE:Remedy for hypertension and cardiac insufficiency. The compound inhibits the angiotensinI II transfer enzyme. It has mild hypotensive activity at the initial stage of the administration, and low side effects. PROCESS:The compound of formulaIis prepared by reacting e.g. the compound of formula R-A<1>-OH (A<1> is glycine residue, sarcosine residue, etc.) with the compound of formula III[R<41> is (protected) OH or alpha-amino acid residue].

Description

Detailed Description of the Invention The present invention is based on the general formula (1) % formula % (wherein R1 is a saturated aliphatic or saturated alicyclic acyl group in which the α carbon is tertiary to quaternary, and M is glycine, sarcosine or an α-D-amino acid residue, R2 means a hydrogen atom or a lower alkyl group, and R means a group represented by the formula.

, the hydrogen atom, the hydroxyl group e-803NH2m is far from the halogen atom), and Y is 10Hj-, -8-, -0-, -80-, -80,- or -〇〇-, and R4 is a hydroxyl group or an α-amino acid residue (α-
bonded via an amino group). The α-amino group contained in A is bonded to R1, and the α-carbonyl group is bonded to the S atom.

When both X and Y are methylene groups, R4 is α-
It is an amino acid residue. ) or a pharmaceutically acceptable salt thereof.

The compound represented by the general formula (1) is a novel compound that has not been published in any literature, and is useful as a medicine.

In general formula (1), the amino acid residues that humans mean are glycine, sarcosine, and α-D-amino acid residues, and examples of --D-amino acids include D-alanine, D- Leucine, D-asparagine, D-methionine, D-glutamine.

D-phenylalanine, D-silibutophane, D-ornithine, D-phenylgutucine, D-zureonine, D-
Glutamic acid, D-fulgiene, D-cysteine, D-
Asparagine fist, D-histidine, D-isolysine,
D-polj, D-lysine, D-serine, D-tyrosine, D-valine, neutral amino acids, acidic amino acids or basic amino acids, or aliphatic amino acids, amino acids having an aromatic ring or a hetero ring, Mention may be made of alicyclic amino acids. Furthermore, the functional groups such as hydroxyl group, mercapto group, amino group, and carboxyl group that these amino acids have are lower alkyl groups and benzyl groups.

It may be substituted with a lower or higher alkanoyl group.

Preferred examples of chemistries include glycine and sarcosine.

D-alanine, 1)-a-isine, D-methionine.

Mention may be made of D-glutamine, D-7:tnylalanine, D-tryptophan, and D-phenylglycine.

The saturated aliphatic or saturated alicyclic acyl group in which the α carbon is tertiary to quaternary as represented by R1 has 4 to 16 carbon atoms,
Preferably it is in the range of 4 to 11, for example Viva p
Examples include yl, cytalobencarboxyl, nyl, cyta-tetrapentanecarbonyl, cyta-tetrahexanecarzanyl, and adamantanecarnyl groups.

The lower alkyl group represented by R2 has 1 carbon number.
~4 may be divided into branches. When R2 is a lower alkyl group, in the structural formula represented by general formula (1), since an asymmetric carbon exists in the group 2-cH26Hco-, DM, L type, and DL type, which is a mixture thereof, exist. . All of these are included within the scope of the present invention, but DM and DL types are particularly preferred.

Examples of the group represented by the formula represented by Rs include the following. Here, the carbon atom to which the group -00R4 is bonded is asymmetric, and there are D-type, L-type, and a mixture thereof, DLII, all of which are included in the scope of the present invention, but Lll and DLM preferable.

・R4 is a hydroxyl group or an α-amino acid residue, and α-
It may be any D-amino acid or α-L-amino acid residue. The α-amino acid residue is bonded to the carbonyl group through its amino group. Examples of α-amino acids are glycine and sarcosine.

Alanine, leucine, methionine, glutamine.

Examples include phenylalanine, tryptophan, and phenylglycine, of which phenylalanine is preferred. In addition, when the above-mentioned X and Y are both methylene groups, R means an α-amino acid residue, and does not include the case where it is a hydroxyl group.

Pharmaceutically acceptable salts of the compound represented by formula (1) include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as IF lucium and magnesium, salts with basic amino acids such as arginine lysine, etc. Among them, calcium salt, 9
Gin salts are preferred.

The compound represented by general formula (1) can be easily produced by several methods.

For example, general formula (1) (wherein AI means glycine, sarcosine or an α-D-acetic acid residue which may optionally have a protecting group). ) or a reactive derivative thereof (wherein X and Y are the same as above; 841 means a hydroxyl group or an α-amino acid residue, which may optionally have a protective group); or a reactive derivative thereof, followed by removing a protective group, if any, from the reaction product, and optionally converting it into a pharmaceutically acceptable salt. be.

The compound represented by the general formula (1) is the compound represented by the general formula (1)
is a functional group that should not participate in the reaction, ie, a mercapto group, a hydroxyl group, or an amino group.

When a group such as a car41r41 syl group is present in a free state, it means a derivative which may be partially protected.

When protecting a functional group present in A1 that should not participate in the reaction, a group that can be removed under relatively mild conditions among the groups commonly used in the field of peptide synthesis is used.

For example, the protection of a mercapto group is a trityl group.

Aralkyl groups such as benzyl and p-methoxybenzyl groups are protected, benzyl groups are used to protect hydroxyl groups, -butyloxycarbonyl groups are used to protect amino groups, and t-butyl groups are used to protect carboxyl groups. Each of them can be used, and their removal can be carried out by the action of hydrogen heptafluoride, trifluoroacetic acid, or hydrogen chloride.

In addition, when R41 in the general formula (II) means a carboxyl group or a protecting group for an α-amino acid residue, the 'i group and the removal means thereof are also the same as those described above.

The reactive derivative of the compound represented by general formula (1) is:
It refers to a derivative in which the carxyl group involved in the reaction is activated. Activation can be achieved by means of activation commonly used in the field of peptide synthesis, such as activated amides, acid halides, active esters, mixed acid hydroxides, etc. This is done by adopting. Among these, preferred examples are acid chlorides, active esters with N-hydroxyconohydric acid imide, mixed acid anhydrides with carbonic acid monoesters, and active amides with carbonyldiimidazole. Caldiimides such as dicyclohexylcarbodiimide can also be used as a condensing agent to form an amide bond between the calxyl group and the imino group. For a compound in which X is -CO- or -08- in general formula (1), an acid halide is used as a reactive derivative of the compound represented by general formula (1).

The reactive derivative of the compound represented by the general formula (sodium carbonate) is
It refers to a derivative in which the imino or amide group of the compound is activated, and activation can be carried out by applying means commonly used in the field of peptide synthesis. For example, when X is other than -co- or -as-, a method of introducing and activating a silyl group such as trimethylsilyl group, a so-called phosphazo method (A
im.

chem, 572 96 (1951)) phosphite method using a phosphite ester such as pyrophosphite tetraethyl ester, and the 11N-carboxy anhydride method (NCA method). can. In addition, when X is -co- or -as-, it can be activated by introducing a silyl group such as a trimethylsilyl group or an alkali metal such as sodium.

The reaction is carried out in an inert organic solvent, e.g.
Dioxane, dimethylformamide, hexamethyl 7-osphotriamide, chloroform.

It is carried out using methane, acetonitrile, benzene, and ether.

The reaction is usually carried out under cooling or heating. That is,
The temperature is usually -50 to 80°C, preferably -20 to 60°C. Specifically, when the compound expressed by general formula (1) is used in the form of an active amide or an acid/%Q compound, -2
0-60℃, -10-10 when used in the form of acid anhydride
°C is preferred.

The reaction time varies depending on the reaction temperature, the compound used in the reaction, the solvent, etc., but is usually selected in the range of 0.5 to 48 hours, preferably 1 to 6 hours.

After carrying out the amide formation reaction, if the product has a protecting group, it is removed. Therefore, the removal can be carried out using the means described above for each protecting group.

Isolation and purification of the target product from the reaction mixture can be carried out according to conventional methods. For example, silica gel.

Various types of talomadography using porous polymers such as dextran crosslinked polymers, styrene-divinylbenzone, or acrylic esters can be applied.

In this case, the solvent is appropriately selected and used from chloroform, ethyl acetate, methanol, ethanol, tetrahydrofuran, benzene, water, acetonitrile, and the like. Also applicable is a method in which the product is isolated in the form of an organic salt such as dicyclohexylamine, and this is treated with an acid such as hydrochloric acid or potassium hydrogen sulfate to liberate the target compound.

When the compound of general formula (1) thus obtained is converted into a pharmaceutically acceptable salt, it is carried out by a conventional method. That is, it is derived by treatment with the above-mentioned base in an amount equivalent to the acidic group in the compound.

Other methods for producing the compound represented by the general formula (1) include the following method. That is, a compound represented by the general formula (N) 8-MOH (wherein R and AL are the same as above) or a reactive derivative thereof, and a compound represented by the general formula (V) (wherein, iL", X, Y 1F K'' (same as above), then removing protective groups, if any, in the reaction product and optionally converting the compound into a pharmaceutically acceptable salt. This is a manufacturing method characterized by conversion.

A in the compound represented by the general formula (R/) is the same as that in the general formula (1), and the protective group that may be present and the means for removing it are also the same as described above. In addition, 1 of the compound represented by the general formula (V)
41 is also the same as that in the general formula (Rin).

The reactive derivative of the compound represented by the general formula (P/) refers to a derivative in which the carboxyl group involved in the reaction is activated, and activation refers to activated aedes, acid halides, activated esters, This is done by taking the form of mixed acid anhydrides, etc. Among these, an active amide with caly=ludiimidazole is one of the preferred examples. Furthermore, it is also possible to carry out the reaction between the carboxyl group and the mercapto group using dirubodiimides such as dicyclohexylcardiimide as a condensing agent.

The reaction between the compound represented by the general formula (P/) or the reactive derivative of the compound represented by the general formula (V) is as follows:
The reaction is carried out in a solvent, and the solvent used is an inert organic solvent such as -tetrahydro7rane, dioxane, dimethyl lumamide, hexamethylphosphotriamide, chloroform, or dichloromethane. The reaction is usually carried out under cooling or room temperature. That is, usually 150
-20°C, preferably -30 to 10°C when the compound represented by the general formula C) is used in the form of an active amide or acid halide, and -10°C when used in the form of an acid anhydride.
-10°C.

The reaction time depends on the reaction temperature, the compound used in the reaction, the solvent, etc., but is usually selected within the range of 0.5 to 48 hours, preferably 1 to 6 hours.

After carrying out the thiol ester forming reaction, if the product has protecting groups, they are removed. Draw and
Its removal can be carried out using the means described above for each protecting group.

Isolation and purification of the target product from the reaction mixture can be carried out according to the conventional methods described above.

Removal of the protecting group is carried out by the conventional method described above.

When the compound of general formula (1) thus obtained is converted into a pharmaceutically acceptable salt, if desired, it is carried out according to the conventional method as already mentioned.

In general formula (1), when R4 means an α-amino acid residue, it can also be produced by the following method.

That is, a compound represented by the general formula (M) octH (in which % R' t A'#♂, X and Y are the same as above) or a reactive derivative thereof, and a compound represented by the general formula (■) H3N-R' ( In the formula, R7 means a residue obtained by removing the a-amino moiety from the α-amino acid residue defined by R4.) The α-amino acid represented by or the functional layer not involved in the reaction is protected. a-amino acids, or their α-
reacting with a reactive derivative at the amino group, then removing the protecting group if present in the reaction product,
This production method is characterized by converting the compound into a pharmaceutically acceptable salt, if desired.

The structure of the compound represented by general formula (M) is the same as that in general formula (1), and the protective group that may be present and the means for removing it are also the same as described above.

The reactive derivative of the compound represented by the general formula (Vl) is
The material is selected from acid halides, fM synthetic acid anhydride, activated esters, m-type acetate, and activated metals commonly used in the field of peptide synthesis. Active esters with N-human gastric xysuccinic acid are one preferred example.

Furthermore, an amide bond can be formed between a carboxyl group and an amino group by using a carbodiimide such as dicyclohexylcarboxylic acid as a condensing agent.

The retention of the functional group that does not participate in the reaction of the α-amino acid represented by the general formula (■) and the means for removing it are shown in the general formula (1).
This is the same as described for Mu1 in .

The above-mentioned reactive derivative of the a-amino group is a derivative in which the amino group is activated, and examples thereof include a method of introducing a silyl group such as a tramethylsilyl group, the so-called sphazo method, the phosphite ester method, the N - Derivatives obtained by applying activation methods commonly used in the field of peptide synthesis, such as the carboxyanhydride method, can be mentioned.

The reaction is carried out in an inert organic solvent, e.g.
Dioxane, dimethylformamide, hexmethyl 7-mole-7-o) lyamide, chloroform.

This is carried out using dichloromethane or the like.

The reaction is usually carried out under cooling or room temperature.

That is, -50 to 30°C, preferably -30 to 20°C
It is.

The reaction time varies depending on the reaction temperature, the compound used in the reaction, the solvent, etc., but is usually selected in the range of 0.5 to 48 hours, preferably 1 to 6 hours.

When the reaction product has a protecting group, its removal, isolation and purification of the target product from the reaction mixture, and conversion to a desired salt can be carried out according to the same conventional methods as described above.

It can be easily produced according to a method using a compound represented by the general formula (1) or a method using a metal compound represented by the general formula (mV).

The object compound of the present invention, that is, the compound represented by general formula (1) and its pharmaceutically acceptable salt inhibits angiotensin-converting enzyme and inhibits angiotensin-converting enzyme.
Since it prevents the production of angiotensin-■ from summer, it is useful in the treatment of hypertensive hypertension caused by the latter, and is also useful as a therapeutic agent for heart failure.

Next, the results of measuring the angiotensin converting enzyme inhibitory activity of some of the target compounds of the present invention are shown.

(1) Measurement method Angiotensin converting enzyme extracted from rabbit lung was used. 0.111 M boric acid-Nmfi003 buffer (
m & 3) 0.6d, 25. , 0.111M boric acid-N containing M benzoylglycylhistidylrecine (substrate)
a2003 buffer (pi(&3) 0.2m and 0.111M phosphoric acid-Na1001 buffer (1!i
&3) Take Q, l- in a test tube and heat it for 5 to 10 minutes at 37℃.
I did a minute Ifl pre-incubation page. Next, a solution of enzyme (acetone powder) extracted from rabbit lungs
1- was added and incubation was performed at 37° C. for 30 minutes. Penzoyldaricin produced by the enzyme was extracted with ethyl acetate under acidic hydrochloric acid and quantified by ultraviolet absorption at 228 m5. The inhibitory activity was determined by setting the enzyme activity without the addition of the test compound as 100, determining the relative activity of the enzyme when the test compound was added, and determining the concentration of the test compound when the relative activity became 50X (lie value). ).

(2) Measurement results Compound jkl
N-(3-(N-sitaνpentankaniponyl-D-atunylthio)-2-D-methylpropanoyl)-L-beaglutaric acid compound hs N-(3-(N-adamantanecarbonylglycylthio)-2 -D-methylpropanoyl)-L-beaglutaric acid compound Ak4 N-(3-(N-cyclohexanecarbunyl-D-alanylthio)-2-D-methylp4panoyl)-L-prolyl-L-phenylalanine compound Ak5 N-(3-(N-citarypancarbonyl-D-phenylalanylthio)-2-D-methylpanoyl)-L-boot-through L-phenylalanine compound 6 -methionylthio)-2-D-methylpropanoyl)-L-pv19-L-7 enylalani compound jlk7 N-
(3-(N-cyclohexanecarbonyl-D-tryptopylthio)-2-D-methylbutanoyl)-L-prolyl-L-phenylalanine compound ks 3-(3-(N-cyclohexanecarbonyl-D-tryptopylthio) )propanoyl]-2-(2-
hydroxyphenyl)-4-thiazolidinecarboxylic acid compound A119 3-(3-(N-cyclopentanecarbonyl-D-alanylthio)propanoyl]-2-(2
-Hydroxyphenyl)-4-thousandaplidinecarboxylic acid compound AklG 3-(3-(N-Vivapyl-D-
Alanylthio)propanoyl)-2-(2-andoxyphenyl)-4-thiazolidinecarboxylic acid The target compound of the present invention is a compound known to have this type of action, such as N-(31-mercapto-2-
Compared to D-methylpropanoyl)-L-propylene (Capbypril), it has superior durability and can be administered in fewer days.
Desirable in terms of self-pressure management.

In addition, the target compound of the present invention is Lancet Lancet Vo1.1+Ak8115, whereas known compounds such as Kab Fp9 have a rapid antihypertensive effect at the initial stage of administration and may cause orthostatic hypotension.

P2S5 (1979, 3, 10)), the target compound of the present invention has a mild hypotensive effect at the initial stage of administration, and orthostatic autohypertension is less likely to occur. Furthermore, drugs having a free mercapto group, such as captopril, exhibit various side effects that are thought to be caused by the mercapto group. For example, taste abnormalities,
The appearance of protein in the urine, granulocytopenia, skin disease accompanied by fever, and others have been reported: 5 Lancet,
Vel, le A & 8160s P2S5
(1980, 1, 19); Oka Te1.2, Ab818
g, P129゜ (1980, 7, 19); South Africa 7 Rican, Medical, Journal 8osIth Afrt
cim Medical Journal Vol.5
8°172 (198G). On the other hand, the object compound of the present invention is unlikely to generate a mercapto group because its thiol ester bond is difficult to undergo hydrolysis in vivo, and therefore may exhibit the above-mentioned side effects that are thought to be caused by the mercapto group. There are few

The proline derivative represented by the general formula (1) and its pharmaceutically acceptable salts can be used in compositions such as tablets, capsules, granules, powders, syrups, and elixirs for oral administration, or parenterally. It can be formulated into a sterile solution or suspension for administration.

For this purpose, one or more of the target compounds of the present invention as active ingredients and excipients used pharmaceutically.

The pharmaceutical composition may include auxiliary agents such as carriers, binders, stabilizers, and flavoring agents.

Oral dosage for adults is usually 0.5'm per day. ~
21, preferably about INg to 500 cm per mouthful.

In the case of parenteral administration, the amount is usually α1 to 600 μ per day, preferably about 0.3 to 5 ooq.

Next, a specific method for producing the compound of the present invention will be explained with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (a) L-pyroglutaric acid (raw material compound 1) L29t was suspended in dry dichloromethane 50, and to this was added 4. Add Of. Then, under stirring, F
Diethylamine2. A 10 d solution of Of in dry dichloromethane is added dropwise and the mixture is heated under reflux for 1 hour. After cooling, 3-(N-
citalohexanecal-D-alanylthio)-2-
D-methylp-tetrabanoyltalolide (raw material compound H)
Add 3.17 F under stirring and stir at room temperature for 2 hours.

Add ice water to the reaction mixture and separate the dichloromethane layer.

The dicool methane layer is washed twice with saturated brine, dried over magnesium sulfate, and then the dicool methane is distilled off. Coat the residue with a silica gel column! Added to thornfish, chloroform-methanol mixture (100:1-100
:3) to collect the 7-lactone containing the target product and distill off the catalyst to obtain N-(3-(N-cyclohexanecalda〇-=8b-5.8.o)-2-D -5, Yapuwaba.

L-L-pyroglutaric acid 0.9F is obtained as a colorless candy. The NMR' of this product (compound 1) is shown in the table below.

0-5 ℃, add 2.15 F of dicitalohexyl lupodiimide under stirring. After stirring overnight at 5°C, insoluble matter was removed. The washing liquid obtained by washing the insoluble matter with a small amount of tetrahydrofuran is combined with the P solution, and the tetrahydro7rane is distilled off. Add 50 d of ethyl acetate to the residue and stir to remove insoluble matter. The F solution is washed successively with 0.5N hydrochloric acid, water, F carbonate water bath solution, and saturated saline, and then dried over magnesium sulfate. When ethyl acetate was distilled off and a mixture of ethyl acetate and hexane (1:1G) was added to the residue, 3-(N-cyclohexanecarbonyl-D-acunylthio)-2-D-methylpropanoic acid and N-human p-oxysuccinic acid were obtained. Active ester with imide 3
．． 45f is solidified and obtained. - Dissolve the above active ester (raw material compound 1f) IF in 30 sl of tetrahydrochloride, and dissolve 0.5 of L-puryl-L-phenylalanine (raw material compound 1) 0.562.
Add 5.2 N sodium hydroxide bath solution and stir at 5°C overnight. The solvent was distilled off from the reaction mixture, 30 ml of water was added to the residue, the volume was adjusted to 1-2 with 2N hydrochloric acid, and extracted with ethyl acetate. Ethyl acetate was distilled off, the residue was subjected to silica gel column chromatography, and chloroform-
Bathe with methanol mixture (100:1 to 100:2). Fractions containing the target product are collected and the solvent is distilled off to obtain N-(3-(N-cyclohexanecarbonyl-
D-alanylthio)-2-D-methylppanoyl]-
0.4f of L-prolyl-L-phenylalanine is obtained as a candy. NMR of this product (compound 4) is shown in the table below.

(c) 3-(N-cyclopropaneyl-D-7enylalanylthio)-2-D-methylpropane acid,
72 f and triethylamine Q, 70 tJ are dissolved in 40 d of dry tetrahydro 7 run, cooled to -10°C, and while maintaining the same temperature, 0.47 d of thalolformic acid ethyl ester is added under stirring.

The Sf reaction solution stirred for 10 minutes at the same temperature is an acid anhydride of propanoic acid and carbonic acid monoethyl ester (raw material compound
).

Dissolve 11.22f of L-prolyl-phenylalanine (INN price compound) in 10wg of 0.5N sodium hydroxide, add this to the above reaction solution kept at -10°C under stirring, and continue stirring for 2 hours. .Tetrahydro7ran was distilled off, 3θMl of water was added to the residue, and -1
1 to 2 and extracted with ethyl acetate. Ethyl acetate was distilled off and the residue was purified by silica gel column chromatography to give N-[3-(N-cyclopropanecarbonyl-D-phenylalanylthio)-2-D-methylpropanoyl]-L -Prolyl-L-7henylashun α852 is obtained as a candy. NMR of this product (compound S) is shown below.

(=)3-(N-cyclohexanecarbo-D-alanylthio)-1-D-methylpanoic acid (raw material compound 1
)1.01? and 1-butyl ester of L-prolyl-L-phenylalanine (raw material compound I)3. Of is dissolved in 50 ml of dry dichloromethane, 2.06 t of dicyclohexylcarbodiimide is added while stirring under water cooling, and stirring is continued for 0.5 hour. After standing overnight at 5°C, the reaction mixture is filtered. Wash the P residue with a small amount of dichloromethane, combine the washing solution with the previous tear fluid, and wash this sequentially with IN hydrochloric acid, water, IN sodium bicarbonate, and saturated saline,
After drying over magnesium sulfate and concentrating under reduced pressure, a gum-like N-(3-(N-citalohexane) is obtained.
atenylthio)-2-D-methylpenitolpanoyl)-L-
t-butyl ester of Pri9-L-phenylalanine 5.7f is obtained.

Dissolve this ester lof in 30 g of anisole,
) Add 1G of 1J fluoroacetic acid and stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove excess trifluoroacetic acid, and the residue was subjected to silica gel column coomadography, followed by chromatography with a chloroform-methanol mixture (100%
:1 to 100:3). When the flattened particles containing the target compound are collected and the solvent is distilled off, N-(3-(N-
hexanecarbonyl-D-7ranylthio)-2-
2.5 tons of D-methylpropanoyl]-L-prolyl-L-phenylalanine are obtained as a colorless candy.

NMR of this product (compound 4) is shown below.

(e) The compounds shown in the table below were obtained using the methods (a) to (d) above.

Example 2 (a) N-cyta-tetrahexene carbonyl-D-afnin (
Raw material compound-1) 5.98F is dissolved in 5OIIL1 of dry tetrahydrol w7 run, cooled to -18°C, and carnyldiimidazole 6.84F is added with stirring. After stirring at the same temperature for about 1 hour, N-(3-mercapto-2-D
Methylpropanoyl)-L-beaglutaric acid (raw material compound-1) & 93F was added, stirred for 30 minutes, and then heated to room temperature.
Stir for 1 hour.

After the reaction is completed, the mixture is concentrated under reduced pressure to distill off the solvent, and 50 ml of water is added to the residue.The mixture is adjusted to a concentration of 1 to 2 with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After adding 12 esutt of a7F nitrile to the residue and dissolving it, diciterhexylamine (DOH) 6I
Add E/ to suspend at room temperature d, heat under reflux for 30 minutes, and then cool. Collect the precipitate and air dry it to form a white D.
OHM salt 110F is obtained.

Suspend 1.52 d of DOH salt in 90 d of ethyl acetate, (
Add L 5 N KH804 aqueous solution 6011i and shake. The organic layer was separated, washed with distilled water, dried over magnesium sulfate, and concentrated under reduced pressure to give N-
(3-(N-Schiff-hexanecarbonyl-D-atenylthio)-2-D-methylpropanoyl)-L-pyroglutal $7.52F is obtained as a gum. This product is NMR
Other properties are the same as Compound 1 obtained in Example 1.

(b) N-cyclohexanecarbonyl-D-alanine (
Raw material compound-1) 1.99F,) ethylamine 0.7
011Ll is dissolved in dry tetrahydrofuran 14w1, cooled to -15°C, and added with stirring ethyl purgerate α48d. After stirring for 15 minutes while maintaining the same temperature,
in(le+-1)3.64f and triethylamine α7
Add 1 OIL of the dried tetrahedron 7 run solution with 0 d. After stirring at the same temperature for 15 minutes, the mixture was further stirred at 5°C overnight. After the reaction was completed, the solvent was distilled off at 30-35°C under reduced pressure, and 1011 L of water was added to the residue.
2 and extracted with chloroform. After washing the separated Tashiroform layer with saturated saline, sulfuric acid! Dry over danesium and then concentrate under reduced pressure. The residue was applied to a silica gel column using chromatography and eluted with 1 t of chloroform-methanol (10:t to 100:3). The 7-lactone containing the target compound was collected and concentrated under reduced pressure to yield N-(3-(N-cyclohexanecarbonyl-D-
alanylthio)-2-D-methylpropanoyl]-L-
Prolyl-L-7enylalanine L2f is obtained as a gum.

This product is the same as Compound 4 of Example 1 based on NMR and other physical properties.

(c) The compounds shown in the table below were obtained using the method (a) or (1-) above. Each of the obtained target compounds was the same as the corresponding compound of Example 1 based on NMR and other physical properties.

59 Implementation @1 (a) N-[3-(N-cytalohexone force luponylu D
-Atenylthio)-2-D-methylpandapanoyl)-L
- 175f of proline (raw material compound-1) and 0.505 F of N-hydroxysuccinimide were dissolved in 35 + lJk1 m of tetrahuman stomach, and while keeping this at 5°C, 0.905 F of dicyclohexylcarbdiimide was dissolved under stirring.
Add 9. Stir overnight at the same temperature and remove the precipitate. The P residue is washed with a small amount of tetrahydrofuran, the washing solution is combined with Solution F, and then the solvent is distilled off. Ethyl acetate is added to the residue to dissolve it, the solution is filtered, and the solvent is distilled off from Solution F to obtain an active ester in the form of a candy (thin layer of silica gel p-mudography klf value 0.64.Developing solvent.

Tarokanform: Methanol: Vinegar #2:1:0.03)
.

The obtained active ester was diluted with tetrahydro7ran 30d&:
To this was added a solution prepared by dissolving 0.725F of L-phenylalanine (WL fee compound 1) and 5d of triethylamine Q in 10d of a water-tetrahuman 07tene mixture (1:1), and the mixture was incubated at 5°C overnight. put.

Tetrahydro 7ran was removed from the reaction mixture, 1011 g of water was added to the residue, and - was adjusted to 1 to 2 with 2N hydrochloric acid.
Extract with ethyl acetate. The organic layer is separated, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and a chloroform-methanol mixture (100:1 to 100
:3). When the 7-lactone containing the target compound was collected and the solvent was distilled off, a candy-like substance N-(3-(N-cyclohexanecarbonyl-D-alanylthio)-2-D
-Methylpropanoyl]-L-prolyl-L-phenylalanine 0.9f is obtained. The silica gel thin layer chromatography R/value of this product is 0.72 (jIk81 solvent, chloroform: methano-/': vinegar #-2:1:0.03
). Furthermore, this product is the same as Compound 4 obtained in Example 1 based on NMR and other physical properties.

(+-) The compounds in the table below were obtained using the above method. Each of the target compounds obtained was the same as the corresponding gold coating of Example 1 from NMR and other characteristics.・Patent applicant Chugai Pharmaceutical Co., Ltd. Continued from page 1 0 Author: Yasuo Fujimura, 3-41-8 Takada, Toshima-ku, Tokyo Chugai Pharmaceutical Co., Ltd. Author: Isao Matsunaga, 3-41 Takada, Toshima-ku, Tokyo No. 8 Chugai Pharmaceutical Co., Ltd. Inventor Tomoyasu Iwaoka No. 41-8 Takada, Toshima-ku, Tokyo No. Chugai Pharmaceutical Co., Ltd. Inventor Noriko Obata Chugai Pharmaceutical Co., Ltd., 3-41-8 Takada, Toshima-ku, Tokyo Inventor: Jun Aono, 3-41-8 Takada, Toshima-ku, Tokyo Inventor: Yoshikazu Hinohara, 3-41-8 Takada, Toshima-ku, Tokyo, Chugai Pharmaceutical Co., Ltd. Inventor: Hideki Nakano, Chugai Pharmaceutical Co., Ltd., 3-41-8 Takada, Toshima-ku, Tokyo Inventor: Seifumi Fukushima, Chugai Pharmaceutical Co., Ltd., 3-41-8 Takada, Toshima-ku, Tokyo Inventor: Hiroyuki Nahata Inventor: Chugai Pharmaceutical Co., Ltd., 3-41-8 Takada, Toshima-ku, Tokyo Inventor: Satoshi Hata, Chugai Pharmaceutical Co., Ltd., 3-41-8 Takada, Toshima-ku, Tokyo No. 41-8 Takada 3-chome Chugai Pharmaceutical Co., Ltd. Internal procedure amendment (method) % formula % 1. Indication of the case 1982 Patent Application No. 140898 2. Name of the invention Thiol ester compound 3. Person making the amendment Case and Relationship: Patent Applicant: 5-5-1 Ukima, Kita-ku, Tokyo (331) Chugai Pharmaceutical Co., Ltd. Representative: Kimio Ueno February 2, 1981 (Delivery date: February 22, 1988) 6. Amendment Description of the subject specification 7, contents of amendment as shown in attached sheet (no change in contents)

Claims (1)

[Claims] l) General formula % formula % (wherein R1 is a saturated aliphatic or saturated alicyclic acyl group in which the α carbon is tertiary to quaternary, A is glycine, sarcosine or α-D-amino acid The residue, R2 means a hydrogen atom or a lower alkyl group, and R3 means a group represented by the formula: hydrogen atom, hydroxyl group + 802NH2, agen atom), and Y is -OH, -, -8-, -0-, -80-, -som- or -C〇-, and s R4 is a hydroxyl group or an α-amino acid residue (α-
bonded through 7 ami groups). The α-ami7 group contained in the group is bonded to B, and the α-carnyl group is bonded to S atom. X
and Y are both methylene groups, R4 is an α-amino acid residue. ) or a pharmaceutically acceptable salt thereof. 2) Claim 1, wherein R3 is the formula! 1) or a pharmaceutically acceptable salt thereof.